Formamidines of primary amines



United States Patent Ofitice Patented Jan. 15, 1963 ,9 FORMAMIDINES OF PRIMARY AMINES Norbert Steiger, Nutley, N.J., assignor to Hoiimann-La Roche Inc., Nutley, N ..l., a corporation of New Jersey No Drawing. Filed Dec. 4, 1957, Ser. No. 700,532

' 8 (Zlaims. (Ci. 260 3976) This invention relates to a process for the production of formamidines from primary amines and to the novel compounds produced by the process.

The process of this invention comprises reacting a non-aliphatic primary amine or a hydrohalide thereof with formamide or -a lower alkyl formamide in the presence of an arylsulfonyl halide or a thionyl halide to produce the formamidine of the primary amine as illustrated by the following reaction schemes:

In the above formulae R represents a cyclic group, X represents halogen and R and R each represents hydrogen or lower alkyl.

The cyclic groups represented by R in the formula above are unsubstituted or substituted monocyclic or polycyclic groups containing five or more atoms and at least one double bond in the ring system. One or more electronegative groups may be attached to the ring. These cyclic groups include aromatic hydrocarbons, hydroaromatic hydrocarbons, nitrogen-, oxygenor sulfur-heterocyclics containing at least one unsaturated linkage, and fused hydrocarbon or heterocyclic ring systems containing at least one unsaturated linkage in the ring system. Illustrative of the different types of cyclic groups, i.e. those represented by R in Formula I, are the following: phenyl, anthraquinone, biphenyl, pyridine, quinoline, pyramidine, isoxazole, thiazole, triazine, uracil, benzothiazole, etc. The ring systems described above may bear one or more substituents, e.g. electronegative acid radicals derived from organic or inorganic acids, such as the halogens, S02, N02, H, SO3H, CHaCO, AS03H2, ester groups such as C H COO. COOC H N(C H acylamino groups such as NHCOCH ether groups such as alkoxy, for example, CH O, C H O, (C H NCH O, alkyl groups, preferably lower alkyl such as methyl, ethyl, propyl, etc.

The primary amino group which takes part inthe condensation reaction must be directly attached to the cyclic portion of the molecule. One or more such primary amino groups present on the nucleus may react. As indicated above, it is also necessary that there be at least one unsaturated linkage in the ring system. The aryl I sulfonyl halide which must be present includes benzenesulfonyl halides, toluenesulfonyl halides, xylenesulfonyl halides, etc., preferably the first two, especially the chlorides thereof. Thionyl halides such as thionyl chloride may also be used. Preferably monoalkyl formamide, such as methyl formamide, and dilower-alkyl formamide, such as dimethylformamide, diethylformamide, etc., are used in the process, lower alkyl formamides, in particular. Compounds bearing very strongly electronegative substituents, e.g. p-nitroaniline, react also with formamide.

When the primary amine contains one or more electronegative substituents on the ring, either the free base itself or its hydrohalide will ordinarily react according to the process of this invention. Strongly basic primary amines, such as amino pyridine, amino quinaldine, aniline, pphenetidine, etc., however, readily form sulfonamides with benzenesulfonyl halides or toluenesulfonyl halides, especially in the presence of an acid binding agent such as pyridine and even formamide or dimethylformamide. In order to produce formamidines from such strongly basic amines according to the process of this invention, it is therefore usually necessary in this instance to use as starting material the hydrohalic salt, preferably the hydrochloride, of the amine. Then the reaction proceeds as in Formula I or Ia above and a formamidine instead of a sulfonamide is obtained.

At least one equivalent of the formamide compound for each reactive amino group is required. Preferably an excess of the formamide compound is used so that it also acts as reaction medium. One equivalent of the sulfonyl halide for each reactive amino group must also be present.

In general the reaction proceeds at room temperature and is exothermic. The primary amine and arylsulfonyl halide or thionyl halide are merely admixed in excess formamide compound, the latter acting also as reaction medium. It is convenient in some instances to apply heat in order to accelerate and complete the reaction, but the temperature should not exceed C.

In many instances the hydrohalide or arylsulfonate salt of the formamidine will precipitate directly from the reaction mixture upon cooling. It is preferable,vhowever, to add to the reaction mixture an inert organic solvent such as alcohol, acetone, benzene, etc., in order to complete the crystallization of the product and to etfect the removal of impurities and excess formamide compound. In general, the stronger amines tend to produce hydrohalic salts and the weaker amines tend to produce sulfonates. The acid salts may be converted to the free base by neutralization with a basic reagent such as aqueous sodium carbonate, sodium hydroxide, etc. Any other acid salt may be obtained from the free base by treatment with an equivalent proportion of the appropriate organic or inorganic.

acid. There may thus be obtained such acid addition salts of the formamidines as the hydrohalides, benzenesulfonates, toluenesulfonates, nitrates, sulfates, phosphates, citrates, tartrates, succinates, etc.

Listed below by structural formula are groups of novel compounds which may be produced according to this invention. The cyclic groups may bear one or more of the substituents described above.

(XVI) R and R, each represents hydrogen or lower alkyl in the above formulae as in Formula I.

Preferred, in the groups listed above, are those compounds having the Formual II wherein the phenyl group is unsubstituted or bears one to three of the acid, ester, ether or acylarnino substituents referred to previously; compounds having Formula III with a p-acylamino group, e.g. acetamino, on the phenyl group; compounds having the Formula V with a hydroxy group or basic ether group, e.g. dilower alkylamino lower alkoxy, in the 6-position; compounds having the Formula VI with one or two of the following substituents: amino, lower alkyl; e.g. methyl, or lower alkoxy, e.g. methoxy; compounds having the Formula VIII with a lower alkyl group, e.g. methyl, on one or both of the phenyl rings; compounds having the Formula IX with a lower alkoxy group, e.g.

methoxy, on each phenyl ring ortho to the formarnidine group; and compounds having the Formula XVI with a lower alkyl group, e.g. methyl, in each of the 3- and 4- positions.

The novel compounds are useful in combatting bacterial, protozoa], viral or helmintic pathogens such as Streptococcus hemolyticus, Diplococcus pneumoniae,

encephalitis Col SK, Mycobacterium tuberculosis, Trichomonas vaginalis, Syphacia abvelata, etc. The compounds may be administered orally or parenterally by incorporating therapeutic doses in conventional vehicles.

The following examples are illustrative of the invention. All temperatures are in degrees centigrade.

Example 1 25 g. of p-diaminodiphenyl-sulfone were dissolved in cc. of dimethylforrnamide. 55 g. of p-toluenesulf onyl chloride were added and the mixture was stirred. The mixture was stirred for about one hour. The temperature rose to 74. The reaction mixture was then poured into 800 cc. of water and 60 cc. of 40% sodium hydroxide. The mixture was stirred for 2 hours and then filtered. The crude crystalline product thus obtained was recrystallized by dissolving in 250 cc. of boiling benzene, filtering off the insoluble impurities and adding 400 cc. of Skellysolve B (an n-hexane fraction) to the benzene filtrate. The mixture was kept overnight in the refrigerator. The crystalline N,N'-(p,p'-sulfonyldiphenylene)bis [N",N"-dimethylformarnidine] thus obtained melted at 131 to 133.

The procedure described in the preceding paragraph was repeated substituting 50 g. of benzenesulfonyl chloride for the 55 g. of p-toluenesulfonyl chloride. The same product was obtained.

100 cc. of dimethylformamide, 25 g. of p-diarninodiphenyl-sulfone and 50 g. of p-toluenesulfonyl chloride were reacted as described in the first paragraph above. After the temperature dropped to 40, 200 cc. of alcohol were added and the mixture was heated to reflux. The clear solution which resulted was filtered while hot. 100 cc. of alcohol were added to the filtrate which was permitted to crystallize in the refrigerator. There was obtained white, crystalline N,N'-(p,p-sulfonyldiphenylene)- bis[N",N"-dirnethylformamidine] p-toluenesulfonate.

Example 2 29 g. of mono-acetyldiamino-diphenyl-sulfone, 50 cc. of dimethylformamide and 22 g. of benzenesulfonyl chloride were stirred together, the temperature rising to 64. The mixture was then stirred for one hour at 60. The reaction mixture was then drowned in 1000 cc. of water. While stirring, cc. of a 20% sodium carbonate solution were dropped in to neutralize the acid. After 24 hours the solid obtained was filtered, the filter cake was washed with ice water and sucked dry on a funnel. The solid was then dried at 70. The p-acetamidophenyl-p- (dimethylaminomethyleneamino)phenyl sulfone was then crystallized from 75% acetic acid, M.P. 260 to 262.

Example 3 27 g. of procaine hydrochloride and 25 g. of p-toluenesulfonyl chloride were stirred in 60 cc. of dimethylformamide. The temperature rose to 45. The mixture was then stirred for 2 hours at 60. The mixture was diluted with 300 cc. of acetone, stirred one hour at room temperature and then chilled to 5. The fl-diethylaminoethylp-(dimethylaminomethyleneamino)benzoate dihydrochloride crystallized as white crystals, M.P. 205 to 206", from isopropanol-ethanol.

Example 4 v 30 g. of p-aminoacetanilide and 50 g. of p-toluenesulfonyl chloride in 70 cc. of dimethylformamide were stirred and heated for one hour in a boiling water bath. The mixture was diluted with 50 cc. of alcohol, refluxed for 1 hours, diluted with 300 cc. of acetone and filtered at 10. The white, crystalline N-(p-acetamidophenyl)- N,N'-dimethylforrnamidine hydrochloride, M.P. 273 to 274, was recrystallized from methanol.

Example 5 28 g. of anthranilic acid and 50 g. of p-toluenesulfonyl The temperature rose to 70.

Example 6 N (p-carboxyphenyl) N',N dimethylformamidine -hydrochloride, obtained as white crystals melting at 236 to 237 upon crystallization from 93% alcohol, was produced from 28 g. of p-azninobenzoic acid according to the procedure described in Example 5.

Example 7 15.5 g. of p-aminosalic'ylic acid and 25 g. of p-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirred together. The temperature rose to 62. The mixture was diluted with 100 cc. of alcohol and permitted to crystallize. The N-(4-carboxy-3-hydroxyphenyl)- N',N-dimethyformamidine p-toluenesulfonate obtained was recrystallized from 90% ethanol, M.P. 235.

Example 8 33 g. of o-aminophenol and 70 g. of p-toluenesulfonyl chloride were reacted in 100 cc. of dirnethylformamide. The mixture was then heated one hour at 85. 25 cc. of alcohol were added to the reaction mixture and it was refluxed for /2 hour. 300 cc. of acetone were added at 40 and the mixture was chilled to 10. The N-(o-hydroxyphenyl)-N,N'- dimethyform-amidine hydrochloride was recrystallized from alcohol and precipitated as white crystals, M.P. 156.

Example. 9

Accordingto the procedure described in Example 8, i

there was obtained from 33 g. of rn-aminophenol, N-(mhydroxyphenyl)-N,N' dimethylforrnamidine hydrochloride as grayish crystals, M.P. 241 upon crystallization from 95% alcohol.

I Example 10 Example 11 18 g. of 4-chloro-2-nitroaniline and 22 g. of p-toluenesulfonyl chloride were stirred in 50 cc. of dimethylformamide, the temperature rising to 51. The mixture was then heated for one hour at 80 to 85 300 cc. of acetone were added at 40 and the precipitate which formed was filtered on. The N,N-dimethyl-N"-(4-chloro-2-nitrophenyl)forrna midine hydrochloride was recrystallized from 95% alcohol, M.P. 205.

Example 12 16 g. of 4-nitro-2-aminotoluene and 25 g. of p-toluene- I sulfonyl chloride were stirred in 50 cc. of dimethylformamide, the temperature rising to 63. The mixture was then stirred at room temperature for one hour. 300 cc. of acetone were added and the mixture was placed in the refrigerator to crystallize. The N,N-dimethyl-N-(2- methyl-S-nitrophenyl)formamidine hydrochloride was recrystallized from 90% alcohol, M.P. 205.

Example 13 17 g. of 4 methoxy 2-nitroaniline and 25 'g. of p-tolu-v enesulfohyl' chloride in 25 cc. of dimethylformamide were reacted as described in Example 12. The N,N-dimethyl- N- 2-nitro-'4-methoxyphenyl) formamidine hydrochloride was crystallized from acetonitrile, M.P. 198 to 200".

Example 14 26 g. of m-chloroaniline and 50 g. of p-toluenesulfonyl chloride in 70 cc. of dimethylformamide were stirred togather, the temperature rising to 74. 100 cc. of alcohol were added, the mixture was heated /2 hour to reflux and then filtered. N-(3-chlorophenyl)-N,N dirnethyl formamidine hydrochloride crystallized from the filtrate. Upon recrystallization from acetonitrile-alcohol, the white crystalline hydrochloride melted at 233.

Example 15 32 g. of 2,5-dichloroa-niline and 50 g. of p-tolu'enesulfonyl chloride in 80 cc. of dimethylformamide were stirred without heating for one hour and then heated for one hour at 90. 150 cc. of alcohol were added, the mixture was refluxed for /2 hour and then filtered. After addition of 300 cc. of acetone to the filtrate, N-(2,5-dichlorophenyl) -N,Nf-dimethylformamidine hydrochloride crystallized. Upon recrystallization from alcohol, the hydrochloride melted at 232.

Example 16 32' g. of 3,4-dichloroaniline and g. of benzenesulfon'yl chloride in 100 cc. of rdimethylformamide were stirred together, the temperature rising to 60. The mixturewas stirred for 2 hours at 60 and then diluted with 300 cc. of acetone. The mixture was then filtered at room temperature. The N-(3,4-dichlorophenyl)-N',N- dirnethylformamidine hydrochloride thus obtained, upon recrystallization from 90% alcohol, melted at 255v to 256.

Example 17 20 g. of 2,4,S trichloroaniline and 25 g. of ptoluenesulfonyl chloride in cc. of dimethylformamide were stirredat room temperature for one hour, then heated at 85 for one hour. The mixture was cooled to 40 and 200 cc.- of acetone were added. Crystalline N,N-dimethyl-N -(2,4',5=trichlorophenyl)formamidine hydrochloride precipitated. The product was filtered, washed with acetone and dried at 70. Upon recrystallization from aces tonitrile-methanol, the product melted at 225 to 227.

The hydrochloride obtained above was dissolved in N sodium hydroxide.

water and made alkaline with 1 The free base, N,N-dimethy1-N'-(2,4,5-trichlorophenyl)- formamidine, was obtained as White after recrystallization from acetonitrile.

Example 18 41 g. of 2,6-dichloro-4-nitroaniline and 42 g. of henzenesulfonyl chloride in 100 cc. of dimethylformamide were stirred together, the temperature rising to 42. The mixture was heated in a water bath for one hour at 90. 50 cc. of alcohol were added, the mixture was refluxed for 15 minutes, cooled to 40 and 400 cc. of acetone were added. The precipitate which formed was filtered, dissolved in 250 cc. of water and 25 cc. of concentrated hydrochloric acid at room temperature and filtered again. The filtrate was neutralized with approximately 40 cc. of sodium hydroxide. The crystalline N,N-dimethyl-'N'- .,(2,6-dich1oro-4 nitrophenyl)forinamidine was recrystal lized from alcohol, M.P. 160 to 162.

Exam le 19 was then heated in a water bath at until a sample, treated with 1 N-HCl and 1 N-NaNO showed no crystals, M.P. 7

diazo reaction. The mixture was cooled to room temperature, 200 cc. of acetone were added and the mixture was stirred in an ice bath. The crystalline N-phenyl- N,N-dimethylformamidine hydrochloride which precipitated was filtered, dried at 75 and recrystallized from isopropanol, M.P. 223 to 225.

The free base, N-phenyl-N',N'-dimethylforrnamidine, was obtained by treating the hydrochloride with a dilute solution of sodium hydroxide, extracting with ether, concentrating the ether solution and distilling the ether concontrate in vacuo. The base was obtained as a colorless oil, B.P. 75 to 75/0.02 mm.

Example 20 35 g. of p-phenetidine hydrochloride and 50 g. of p-toluenesulfonyl chloride in 60 cc. of dimethylformamide were stirred together, the temperature rising to 64. The diazo reaction of the mass was negative. The mixture was diluted with 400 cc. of acetone and placed in the refrigerator to crystallize. The mixture was filtered and the N-(pethoxyphenyl)-N',N'-dimethylformamidine p-toluenesulfonate was recrystallized from isopropanol, M.P. 169 to 170.

Example 21 28 g. of o-nitroaniline and 45 g. of p-toluenesulfonyl chloride in 100 cc. of dimethylformamide were stirred together, the temperature rising to 60. The mixture was then stirred and heated in a water bath for one hour at 90 to 95; The reaction mixture was then diluted at 80 with 300 cc. of benzene and chilled to The N-(onitrophenyl)-N,N-dirnethylformamidine hydrochloride which precipitated was filtered off, washed with benzene and recrystallized from acetonitrile-ethanol, M.P. 224 to 225.

Example 22 28 g. of m-nitroaniline and 45 g. of p-toluenesulfonyl chloride in 100 cc. of dimethylformamide were stirred together, the temperature rising to 62. The mixture was then heated for 2 hours at 90 to 95, 200 cc. of alcohol were added and the mixture was refluxed for /2 hour. The clear solution was filtered through a folded filter. N (m-nitrophenyl)-N,N'-dimethylformamidine hydrochloride crystallized from the filtrate. Upon recrystallization from 90% alcohol, the compound melted at 248 to 250".

Example 23 28 g. of p-nitroaniline and 45 g. of p-toluenesulfonyl chloride in 150 cc. of dimethylformamide were stirred together, the temperature rising to 62. perature .had fallen to 40, the reaction mixture was heated at 85 for one hour. The mixture was diluted with 300 cc. of alcohol, refluxed until a clear solution was obtained and the solution was filtered hot. The N- (p-nitrophenyl) -N,N-dimethylformamidine p-toluenesulfonate crystallized from the filtrate, M.P. 240 to 242.

42 g. of N-(p-nitrophenyl)-N',N-dimethylformamidine p-toluenesulfonate were dissolved at 90 in 500 cc. of water and the solution was filtered while hot. The filtrate was made alkaline with about 30 cc. of sodium hydroxide. The free base, N-(p-nitrophenyl)-N,N-dimethylformamidine, precipitated and was recrystallized from benzene-Skellysolve B, M.P. 79 to 80.

Example 24 22 g. of arsanilic acid and 50 cc. of dimethylformamide were stirred together. 25 g. of p-toluenesulfonyl chloride were added with the temperature rising to 60. The reaction mixture was heated for one hour at 80, /2 hour at 95 and another half hour at 105. The mixture was cooled to 30, diluted with 250 cc. of acetone and then chilled to The mixture was filtered after 2 hours and the residue was washed with acetone. The 4-(N,N- dimethylformarnidino)benzenearsonic acid hydrochloride was crystallized from dilute alcohol, M.P. 221 to 222.

When the tem- Example 25 20 g. of l-amino-anthraquinone and 30 g. of p-toluenesulfonyl chloride in 100 cc. of dimethylformamide were heated at for one hour. The mass was diluted with 250 cc. of alcohol, refluxed until a clear solution was obtained and filtered while hot. 1-(N,N-dirnethylformamidino)anthraquinone toluenesulfonate crystallized from the filtrate, M.P. 185.

Example 26 18 g. of sulfanilic acid and 22 g. of p-toluenesulfonyl chloride in 60 cc. of dimethylformamide were stirred together, the temperature rising to 55. The mixture was heated one hour at 80. The diazo reaction was negative. The mixture was diluted at 80 with cc. of alcohol and stirred for one hour, then filtered at 10. The N (dimethylaminomethyleneamino)sulfanilic acid was crystallized from 60% alcohol, M.P. 308 (with dec.).

Example 28 17 g. of dianisidine hydrochloride and 20 g. of benzenesulfonyl chloride in 50 cc. of dimethylformamide were stirred at room temperature for one hour, then heated at 85 for an additional hour. The diazo reaction was then negative. The mixture was diluted at 60 with 200 cc. of acetone, cooled to 10 and filtered. The N,N'- bis[dimethylaminomethylene] 4,4 o dianisidine dihydrochloride was crystallized from alcohol, M.P. 268' (with dec.).

Example 29 24 g. of p-aminoazobenzene hydrochloride and 25 g. of p-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirred together, the temperature rising to 56. The mixture was heated for /2 hour at 80, diluted with 175 cc. of alcohol, heated to reflux for /2 hour and the clear solution was then filtered while hot. p-(Dimethylaminomethyleneamino)azobenzene p toluenesulfonate crystallized from the filtrate, M.P. 198 to 199'.

Example 30 Hydrogen chloride gas was passed into a suspension of 47 g. of Z-aminopyridine in 300 cc. of toluene at a temperature of 5 to 15 C. until saturated. 2-aminopyridine dihydrochloride separated as an oil. The oil was added to 200 cc. of dimethylformamide. g. of p-toluenesulfonyl chloride were added with stirring. The mixture was stirred at room temperature for one hour and then at 60 for 2 hours. It was then cooled to 20, diluted with 400 cc. of acetone and chilled to 10. The white, crystalline 2-(N,N-dixnethylformamidino)pyridine dihydrochloride was then filtered off and recrystallized from methanolacetone, M.P. 178.

Example 31 was stirred for one hour and then filtered at 10. The

filter cake was dried in a desiccator over sulfuric acid. The 2,6-bis-(N,N-dimethylformamidino)pyridine dihydrochloride was crystallized from methanol-acetone, MP. 289 to 290.

Example 32 26 g. of 6-methoxy-8-aminoquinoline hydrochloride and 25 g. of benzenesulfonyl chloride in 100 cc. of dimethylformamide were stirred together, the temperature rising to 61. The mixture was heatedat 80 for one hour, diluted at 60 with 300 cc. of acetone, chilled to 10 and filtered. The 6-methoxy-8-(dimethylaminomethyleneamino)quinoline dihydrochloride, upon crystallization from 90% alcohol, melted at 210 to 212.

The free base, 6-methoxy-8-(dimethylaminomethyleneamiuo)quinoline, was obtained by dissolving the dihydrochloride obtained above in water and making the solution alkaline with 1 N sodium hydroxide. The free base crystallized from acetonitrile in the "form of white needles, M.P. 158.

Example 33 alkaline with sodium hydroxide. The free base was obtained as off-white crystals upon crystallization from acetonitrile, M.P. 223 to 224.

Example 34 26 g. of Z-aminopyrimidine hydrochloride and 42 g. of benzenesulfonyl chloride in 50 cc. of dimethylformamide were stirred together, the temperature rising to 41. The mixture was heated at 90 for one hour and then diluted at 40 with 300 cc. of acetone. N,N-dimethyl-N-(2- pyrimidyl)formamidine hydrochloride crystallized and was filtered at 10. The hydrochloride was recrystallized from acetonitrile, M.P. 212.

Example 35 23 g. of 5-amino-3,4-dimethylisoxazole and 50 g. of ptoluenesulfonyl chloride in 50 cc. of dimethylformamide were stirred together, the temperature rising to 75. The mixture was heated for one hour at 85. It was then diluted at 30 with 400 cc. of acetone and filtered at The residue, N,N-dimethyl-N-(3,4-dimethyl-5-isoxazolyl)formamidine p-toluenesulfonate was crystallized from alcohol, M.P. 145.

Example 36 g. of 2 aminothiazole and 50 g. of p-toluenesulfonyl chloride in 50' cc. of dimethylformamide were stirred together, the temperature rising to 61. The mixture was heated for /2 hour at 85. It was then diluted with 400 cc. of acetone at 60 and chilled to 10. The white, crystalline N,N-dimethyl-N'-( 2 thiazolyl)formarnidine hydrochloride was filtered and recrystallized from isopropanol-acetone, M.P. 168 to 170.

Example 37 21 g. of N,N-diallylmelamine and 25 g. of p-toluenesulfonyl chloride in 100 cc. of dimethylformamide were stirred for one hour at room temperature. The mixture was heated for /2 hour at 60, one hour at 80 and then /2 hour at 85. At room temperature it was diluted with 300 cc. of water and cc. of sodium hydroxide. The mixture was stirred for-2V2 hours at room temperature and the white precipitate was then filtered elf. The 2-diallylamino-4-amino-6-(N,N dimethylformamidine)- S-triazine was crystallized from acetonitrile, M.P. 174.

. crystalline base melted at 59 to 60.

10 Example 38 2.5 g. of S-arninouracil and'5 g. of p-toluenesulfonyl chloride and 6 cc. of dimethylformamide were heatedin a water bath at The meltwas diluted with 4 'cc. of alcohol and 20 cc. of acetone. The precipitated S-(dimethylaminomethyleneamino)-2,4, dioxo 1;2,3,4-tetrahydropyrimidine hydrochloride was filtered at 10 and crystallized from 85% ethanol, M.P. higher than 350".

Example 39 Example 40 20 g. of p-nitroaniline, 35 g. of p-toluenesul'fonyl chloride and 50 cc. of diethylformamide were heated in a boil ing water bath for one hour until a clear light yellow solution was formed. The solution was diluted with cc. of alcohol, heated to reflux for 15 minutes and filtered.

while hot. The filtrate was cooled to 10 and 200 cc. of ice water were added. N-(p-nitrophenyl)-N,N'-diethyl formamidine p-toluenesulfonate crystallized in needles. The compound was filtered, washed with a little ice water, dried in the oven and recrystallized from dilute alcohol, M.P. to 162.

The free base, N-(p-nitrophenyl)-N,N -diethylformamidine, was obtained by dissolving the p-toluenesulfonate in water, filtering and making the filtrate alkaline with aqueous sodium carbonate solution. The yellow,

Example 41 2 g. of p-nitroaniline, 3.5 g. of p-toluenesulfonyl chloride and 5 cc. of methylformamide were heated for /2 hour in a boiling water bath. The mixture was diluted with 15 cc. of alcohol, heated until solution was obtained and then filtered while hot. N-(p-nitrophenyl)-N-methylformamidine p-toluenesulfonate crystallized from the filtrate. Upon recrystallization from alcohol, the COHI'. pound melted at Example 42 41 g. of 2-amino-6-hydroxybenzothiazole and 50 g. of p-toluenesulfonyl chloride in 100 cc. of dimethylformamide were stirred together, the temperature rising to 65 The mixture was heated and stirred for 2 hours at 80. It was diluted at 60 with 300 cc. of acetone. 2-(N,N-dimethylformamidino)-6-hydroxybenzothiazole hydrochloride precipitated, was filtered and dried, M.P. 230.

15 g. of the hydrochloride obtained above were dissolved in 200 cc. of water at 60 and filtered. 50 cc. of

sodium acetate solution (20%) were added'to the filtrate.

The free base, 2-(N,N dimethylformamidino)6-hydroxybenzothiazole, precipitated, was filtered oil and dried, M.P. 237. Example 43 2.2 g. of 2-(N,'N-dimethylformamidino)-6 hydroxybenzothiazole, 300 cc. of chlorobenzene, 7 g. of sodium methoxide and 50 cc. of methanol were stirred for one hour at room temperature. The methanol was then distilled ofi. 20 g. of diethylaminoethyl chloride were added at 90 and the reaction mass was heated for 3 hours to reflux at 130. It was then cooled below 100, 200 cc. of water and 10 cc. of sodium hydroxide were added and the mixture was stirred for one hour. The chlorobenzene layer The crystalline precipitate,

was separated, dried with sodium sulfate, filtered and concentrated in vacuo. The oily residue was crystallized from acetonitrile and recrystallized from benzine (B.P. 30 to 60). The yellow crystalline 2-(N,N-dimethylformamidino)-6-(fi-diethylaminoethoxy)benzothiazole melted at 69 to 70.

The free base obtained above was converted into the oxalate by mixing an ether solution of the base with an ether solution of oxalic acid. The oxalate precipitated and was crystallized from methanol, M.P. 162 to 163.

Example 44 34 g. of 3-aminopyridine dihydrochloride and 45 g. of p-toluene-sulfonyl chloride in 100 cc. of dimethylformamide were stirred together, the temperature rising to 71. The mixture was heated for one hour at 80. It was diluted at 40 with 300 cc. of acetone and chilled to 3-(N,N-dimethylformamidino) pyridine dihydrochloride, was filtered and recrystallized from methanol-ethanol, M.P. 228 (with dec.).

Example 45 26 g. of 4-aminopyridine hydrochloride and 44 g. of ptoluene-sulfonyl chloride in 100 cc. of dimethylformamide were stirred together, the temperature rising to 38. The mixture was heated for 2 hours at 60. A sandy precipitate formed. The mixture was diluted with 300 cc. of acetone, chilled to 10 and filtered. 4-(N,N-dimethylformamidino) pyridine dihydrochloride was obtained as white crystals, M.P. 260 to 261 (with dec.), upon crystallization from methanol-acetonitrile.

Example 46 25 g. of p-diamino-diphenyl-sulfone and 50 cc. of dimethylformamide were stirred. 26 g. of thionyl chloride were dropped in at a temperature below The mixture was stirred for one hour at room temperature, 2 hours at 60 to 65 and 2 hours at 80 to 90. The diazo reaction was negative. The mixture was diluted at room temperature with 150 cc. of water and filtered through a folded filter. The filtrate was made alkaline with sodium hydroxide. The white precipitate, N,N-(p,p'-sulfonyldiphenylene)bis[N",N"-dimethylformamidinel, was filtered, washed with water, dried and crystallized from Skellysolve C (a normal heptane fraction), M.P. 130 to 133.

Example 48 22 g. of p-aminophenol and 50 cc. of dimethylformamide were stirred. 26 g. of thionyl chloride were dropped in at a temperature below 20. The mixture was stirred for one hour at room temperature, then heated one hour at 60, one hour at 80 and 2 hours at 95. The diazo reaction was negative. The mixture was diluted with cc. of alcohol and 200 cc. of acetone. An additional 400 cc. of acetone were added and the mixture was placed in the refrigerator to crystallize. The N-(p-hydroxyphenyl)-N',N-dimethylformamidine hydrochloride was recrystallized from methanol-acetone, M.P. 198 to 200. By treatment of the hydrochloride with sodium carbonate solution, N (p-hydroxyphenyl)-N,N'-dimethylformami dine precipitated. The free base was crystallized from alcohol, M.P. 197 to 199'.

Example 49 69 g. of p-phenetidine hydrochloride and 100 cc. of

dimethylformamide were stirred. 52 g. of thionyl ride were dropped in at a temperature below 20. The temperature were permitted to rise slowly to 30. The mixture was then heated in a water bath to 40, one hour at 60, one hour at and one hour at The diazo reaction was then negative. The mixture was diluted with 200 cc. of water and then made alkaline at 15 to 22 with cc. of sodium hydroxide and 25 cc. of sodium carbonate (20%). 300 cc. of other were added. The ether layer was separated, chilled in an ice bath and 20 g. of concentrated sulfuric acid were added. The ether was decanted oil. The residue was crystallized from 200 cc. of acetonitrile and filtered. The N-(p-ethoxyphenyl)- N, N'-dimethylformamidine sulfatemelted at 158 to 160.

Example 50 42 g. of p-nitroaniline and 100 cc. of dimethylform amide were stirred. 39 g. of thionyl chloride were added at a temperature below 20. The mixture was heated to 30 and the temperature then rose to 68. N-(p-nitrophenyl)-N,N'-dimethylformamidine hydrochloride crystallized. The mixture was diluted with 400 cc. of acetone and filtered. The residue was sucked dry on a funnel and then dried in a desiccator over sulfuric acid. The product was recrystallized from alcohol, M.P. 261.

Example 51 45 g. of 4-o-tolylazo-o-toluidine and 100 cc. of dimethylformamide were stirred. 26 g. of thionyl chloride were added at a temperature below 20. The mixture was stirred at room temperature and then the temperature rose to 48. The diazo reaction was negative. The mixture was stirred for an additional 2 hours at room temperature, then 300 cc. of acetone were added. The 5-0- tolylazo 2 (N,N dimethylformamidino) toluene hydrochloride was filtered ofi, M.P. 198 to 200.

I claim:

1. A member of the group consisting of compounds of the formula R: wherein R and R each represents a member of the group consisting of hydrogen and lower alkyl,

and acid salts of said compounds.

2. A member of the group consisting of compounds of the formula wherein R and R each represents a member of the group consisting of hydrogen and lower alkyl,

HGON

wherein R and R each represents a member of the group consisting of hydrogen and lower alkyl,

chloin the presence of at least one equivalent for each reac- 1 H C O N- wherein R and R each represents a member of the group consisting of hydrogen and lower alkyl,

in the presence of at least one equivalent for each reaetive amino group of a member of the group consisting of a phenylsulfonyl halide and thionyl halide.

7. A process for the production of formamidines which comprises reacting at temperatures between about room temperature and 100 C. the hydrohalide salt of a basic aromatic primary amine with at least one equivalent of dialkylformamide in the presence of at least one equivalent of a phenyl sulfonyl halide and neutralizing the reaction product.

8. A process for the production of formamidines which comprises reacting at a temperature between about room temperature and 100 C. the hydrohalide salt of 3 a basic aromatic primary amine with at least one equiva I lent of dimethylformamide in the presence of at least one equivalent of p-toluenesulfonyl chloride and neutralizing the reaction product with sodium hydroxide.

References Cited in the file of this patent UNITED STATES PATENTS 2,207,045 Wilder et a1. Ju1y 9, 1940 2,413,833 Kyrides Jan. 7, 1947 2,512,249 Hultquist June 20, 1950 2,566,226 Mackay Aug. 28, 1951 2,578,178 Derbyshire Dec. 11, 1951 2,617,809 Hubbard Nov. 11, 1952 2,640,830 Druey June 2, 1953 2,692,284 Haury Oct. 19, 1954 2,715,625 Maxwell Aug. 16, 1955 2,763,660 Young Sept. 18, 1956 2,823,202 Thelin Feb. 11, 1958 OTHER REFERENCES J. Am. Chem. Soc., vol. 76, pages UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 O73,85l January 15, 1963 Norbert Steiger fied that error appears in the above numbered pat- It is hereby certi said Letters Patent should read as ent requiring correction and that the corrected below.

Column 2, lines 66 to 72, formula (VI) should appear as shown below instead of as in the patent:

column 3, line 56, for "Formual" read Formula column 7, line 12, for "75 to 75 read 75 to 76 column 12, line 3, for "were" read was Signed and sealed this 19th day of November 1963.,

(SEAL) Attest: EDWIN L. REYNOLDS ERNEST W. SWIDER I Attesting Officer Actin Commissioner of Patents 

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA
 5. A PROCESS FOR THE PRODUCTION OF FORMAMIDINES WHICH COMPRISES REACTING AT A TEMPERATURE BETWEEN ABOUT ROOM TEMPERATURE AND 100* C. A CYCLIC PRIMARY AMINE, CONTAINING DIRECTLY ATTACHED TO THE AMINO GROUP AN UNSATURATED CYCLIC RADICAL WITH AT LEAST 5 CARBON ATOMS AND AN ELECTRONEGATIVE SUBSTITUENT THEREON, WITH AT LEAST ONE EQUIVALENT FOR EACH REACTIVE AMINO GROUP IN SAID AMINE OF THE FORMAMIDE HAVING THE FORMULA 